Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells
Sandra Valle, Sonia Alcalá, Laura Martín-Hijano, Pablo Cabezas‐Sainz, Diego Navarro, Edurne Ramos Muñoz, Lourdes Yuste, Kanishka Tiwary, Karolin Walter, Laura Ruíz-Cañas, Marta Alonso‐Nocelo, Juan A. Rubiolo, Emilio González‐Arnay, Christopher Heeschen, Laura García‐Bermejo, Patrick Hermann, Laura Sánchez, Patricia Sancho, Miguel Ángel Fernández‐Moreno, Bruno Sáinz
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7-9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.